MXPA03011627A

MXPA03011627A - Stereoselective method for the preparation of nucleoside analogues.

Info

Publication number: MXPA03011627A
Application number: MXPA03011627A
Authority: MX
Inventors: Yu Qing
Original assignee: Shire Biochem Inc
Priority date: 2001-06-15
Filing date: 2002-06-14
Publication date: 2005-03-07
Also published as: HRP20031021B1; EA006372B1; DK1406896T3; CA2449338A1; DE60208202D1; EP1406896B1; JP4542776B2; JP2004535428A; US7109334B2; AU2002344862C1; AU2008203443A1; CN1543463A; DE60222031D1; AU2002344862B2; ES2293445T3; CA2449338C; US7230100B2; EP1632490B1; ATE313542T1; YU97503A

Abstract

A process for producing predominantly cis nucleosides or nucleoside analogues and derivatives of formula (A): wherein R1 is a pyrimidine base or a pharmaceutically acceptable derivative thereof and Q is oxygen, carbon or sulphur, comprising a coupling step of the pyrimidine base with a molecule of formula (B) described herein in a suitable coupling solvent, in the presence of catalytic amounts of an element or combination of elements of groups 1B or 11B of the periodic table, a tertiary amine and a Lewis acid to obtained an intermediate of formula (D) which is deprotected in the subsequent step to generate the product of formula (A).

Description

ESTER EOS ELECTIVE METHOD FOR THE PREPARATION OF NUCLEOSIUM ANALOGS The present invention relates to a novel process for producing cis-nucleosides or nucleoside analogues and derivatives of the formula (A): wherein R1 is a pyrimidine base, or an acceptable derivative for pharmaceutical use, and Q is oxygen, carbon or sulfur. It has been found that the classes of compounds of the formula (A), in particular the 2-substituted, 4-substituted 1, 3-oxathiolanes, have potent antiviral activity. In particular it has been found that these compounds act as potent inhibitors of HIV-1 reproduction in T lymphocytes, for a prolonged period of time, with fewer cytotoxic side effects than the compounds known in the art (see Belleau and coauthors (1993)). Bioorg, Med. Chem. Lett., Volume 3, No. 8, pages 1723-1728). It has been found that these compounds are also active against HIV strains resistant to 3TC (see Taylor and co-authors (2000) Antiviral Chem. Chemother., Volume 11, No. 4, pages 291-301; Stoddart and co-authors (2000) Antimicrob. Agents Chemother., Volume 44, No. 3, pages 783-786). These compounds are also useful in the prophylaxis and treatment of hepatitis B virus infections.

Methods for the preparation of these compounds have been described in the publications of TCP No. WO 92/08717 and WO 95/29176, as well as in publications by Belleau and coauthors (1993), Bioorg. Med. Chem. Lett., Volume 3, No. 8, pages 1723-1728; Wang and co-authors (1994) Tetrahedron Lett., Volume 35, No. 27, pages 4739-4742; Mansour and coauthors (1995), J. of Med. Chem., Volume 38, No. 1, pages 1-4; and Caputo and coauthors, in Eur. J. Org. Chem., Volume 6, pages 1455-1458 (1999). These processes involve a multitude of steps that increase production costs and reduce the performance of the desired compounds.

BRIEF DESCRIPTION OF THE INVENTION The process constituting the object of the present invention comprises the step of coupling the intermediate of formula (B): wherein: R 2 is hydrogen or a hydroxyl protecting group, such as arylalkyl of 7 to 10 carbon atoms, acyl of 1 to 16 carbon atoms or Si (Z 1) (Z 2) (Z 3), wherein Z, Z 2 and Z3 are independently selected from the group consisting of hydrogen, alkyl of 1 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine, iodine, alkoxy of 1 to 6 carbon atoms or aryloxy of 6 to 20 carbon atoms; aralkyl of 7 to 20 carbon atoms, optionally substituted with halogen, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; aryl of 6 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine, iodine, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; trialkylsilyl; fluorine; bromine; chlorine and iodine; and Q is carbon, oxygen or sulfur; with R1, a pyrimidine base or a pharmaceutically acceptable derivative, in the presence of a catalytic amount of an element, or of a combination of elements of group IB or IIB, a Lewis acid and a tertiary amine. The resulting intermediate, of formula (D), is deprotected: to obtain the cis-nucleoside of the formula (A) The compound of the formula (B) can be (B1): or (B2): or a mixture of the two enantiomers. In an alternative embodiment of the present invention, deprotection of the intermediate of the formula (D) is obtained by dissolving said intermediate in a suitable solvent, in the presence of a deprotection agent. In an alternative embodiment of the present invention there is provided a simple two step preparation method for the cis-nucleosides of the formula (A), where the coupling step results in a product in which the cis to trans ratio is higher 2 to 1. In another embodiment, the cis to trans ratio of the intermediate product of the formula (D) is inversely proportional to the reaction temperature in the coupling step. In an alternative embodiment of the present invention the deprotection step results in the selective precipitation of the cis-nucleoside of the formula (A) by the selection of an appropriate deprotection agent and a solvent. The processes of the present invention have the advantages of allowing the preparation of a nucleoside of the formula (A), its analogues or its derivatives, without the use of expensive starting materials, difficult protection and deprotection stages, or additions or elimination of the 2 'or 3' substituents. The process of the present invention produces cis-nucleosides of the formula (A) in high yields, with high purity and high stereoselectivity. The process of the present invention has the additional advantage of generating nucleosides whose stereochemical configuration can be easily controlled, simply, by selecting the appropriate starting conditions.

DETAILED DESCRIPTION OF THE INVENTION The present invention describes a stereoselective process for preparing predominantly cis-nucleosides or analogs and nucleoside derivatives of the formula (A): wherein: R1 is a pyrimidine base or a derivative thereof acceptable for pharmaceutical use; and Q is carbon, oxygen or sulfur; which consists of the coupling step of a formula compound (B): wherein: R2 is hydrogen or a hydroxyl protecting group, such as aralalkyl of 7 to 10 carbon atoms, acyl of 1 to 16 carbon atoms or Si (Z1) (Z2) (Z3), where Z Z2 and Z3 they are independently selected from the group consisting of hydrogen; alkyl of 1 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine, iodine, alkoxy of 1 to 6 carbon atoms or aryloxy of 6 to 20 carbon atoms; aralkyl of 7 to 20 carbon atoms, optionally substituted with halogen, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; aryl of 6 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine, iodine, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; trialkylsilyl; fluorine; bromine; chlorine and iodine; with a base R1, wherein R1 is a pyrimidine base or a derivative thereof acceptable for pharmaceutical use; in a suitable coupling solvent, in the presence of a catalytic amount of an element or a combination of elements of group IB or IIB; a tertiary amine and a Lewis acid of the formula (C): R4 I R7 - Si - R5 I R6 (C) wherein: R4, R5 and R6 are independently selected from the group consisting of hydrogen; alkyl of 1 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine, iodine, alkoxy of 1 to 6 carbon atoms or aryloxy of 6 to 20 carbon atoms; aralkyl of 7 to 20 carbon atoms, optionally substituted with halogen, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; aryl of 6 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine, iodine, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; trialkylsilyl; fluorine; bromine; chlorine and iodine; and R7 is selected from the group consisting of fluorine; bromine; chlorine; iodo; sulfonate esters of 1 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine or iodine; alkyl esters of 1 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine or iodine; triiodide; a silyl group of the general formula (R4) (R5) (R6) Si (where R4, R5 and R6 are as defined hereinabove); arylselenenyl of 6 to 20 carbon atoms; arylsulfenyl of 6 to 20 carbon atoms; alkoxyalkyl of 6 to 20 carbon atoms; and trialkylsiloxy; to produce an intermediate of the formula (D): The coupling step is followed by a deprotection step to produce the cis-nucleosides or the nucleoside analogues or derivatives of the formula (A). In an alternative embodiment, the present invention contemplates a simple, two step preparation method for preparing nucleosides of the formula (A), wherein the process results in a product of the formula (A) in which the cis to trans is greater than 2 to 1. The invention includes a process in which the cis to trans ratio is greater than, or equal to, 3 to 1. The term "alkyl, when used herein, unless specified otherwise, it refers to a straight, branched or cyclic primary, secondary or tertiary saturated hydrocarbon, of 1 to 30 carbon atoms, particularly of 1 to 6 carbon atoms, unsubstituted or monosubstituted or optionally disubstituted with hydroxy , N3, CN, SH, amino, halogen (F, Cl, Br, I), aryl of 6 to 12 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms or nitro. specifically: methyl, ethyl, cyclopropyl, propyl, isopropyl, butyl, isobutyl, butyl tertiary, pentyl, cyclopentyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, cyclohexylmethyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.

The term "acyl", when used in what follows, refers to a functional group derived from an aliphatic carboxylic acid, by elimination of the -OH group, from 1 to 30 carbon atoms, particularly from 1 to 6 carbon atoms. carbon As the acid to which it is related, the aliphatic acyl radical can be substituted (with a hydroxyl, N3, CN, halogen (F, Cl, Br, I), aryl of 6 to 12 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms or nitro), or unsubstituted, and whatever may be the structure of the rest of the molecule, the properties of the functional group remain essentially unchanged (for example, acetyl, propionyl, isobutanoyl, pivaloyl, hexanoyl, butyryl, pentanoyl, 3-methylbutyryl, bisuccinate, mesylate, valeryl, caproic, caprylic, capric, lauric, myristic, palmitic, stearic, oleic, 3-cyclobenzoate, trifluoroacetyl, chloroacetyl, and cyclohexanoyl). alqu "enyl" and "alkynyl" represent straight, branched or cyclic hydrocarbon chains, substituted (with N3, CN, halogen, hydroxyl or aryl of 6 to 20 carbon atoms), having from 2 to 30 carbon atoms and, preferably, , from 2 to 6 carbon atoms, and containing at least one unsaturated group (for example, allyl). The term "alkoxy" represents a substituted or unsubstituted alkyl group, of 1 to 30 carbon atoms and, preferably, of 1 to 6 carbon atoms, wherein the alkyl group is covalently linked to an oxygen atom (eg, example, methoxy or ethoxy).

The term "aryl" represents an aromatic portion which may be mono-, bi-, tri-, tetra- or penta-substituted by hydroxy, nitro, N3, CN, halogen (F, Cl, Br, I) or combinations thereof, and which contains at least one ring of the benzenoid type; the group may contain from 6 to 14 carbon atoms (for example, phenyl and naphthyl), in particular from 6 to 10 carbon atoms. The term "aryloxy" represents an aryl substituted portion (with a halogen, trifluoromethyl or alkoxy of 1 to 5 carbon atoms) or unsubstituted, having 6 to 14 carbon atoms, covalently bound to an oxygen atom (e.g. , benzyloxy, phenoxy). The term "aralalkyl" represents a substituent comprising an aryl moiety attached by means of an alkyl chain (eg, benzyl, phenylethyl), where the total sum of the carbon atoms of the aryl portion and the alkyl chain is 7 to 21. The aryl portion or the chain, of the group, is optionally substituted once or twice with OH, SH, amino, halogen or alkyl of 1 to 6 carbon atoms. The term "thiol" represents alkyl groups of 1 to 6 carbon atoms, aryl of 6 to 15 carbon atoms, aralkyl of 7 to 21 carbon atoms, alkenyl of 2 to 6 carbon atoms or alkynyl of 2 to 6 carbon atoms carbon, covalently bonded to an adjacent sulfur atom containing a hydrogen. The terms "alkylthio" (e.g., methylthio, ethylthio) and "arylthio" (e.g., phenylthio, benzylthio), refer to alkyl groups of 1 to 6 carbon atoms or aryl of 6 to 10 carbon atoms, unsubstituted or monosubstituted or optionally disubstituted with hydroxy, halogen (F, Cl, Br, I), aryl of 6 to 12 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxyalkyl of 2 to 12 carbon atoms or nitro; covalently bound to an adjacent sulfur atom. The terms "acyloxy" and "alkoxycarbonyl" refer to chains of 1 to 30 carbon atoms, in particular of 1 to 6 carbon atoms, which are saturated or unsaturated, and which may also be straight or branched (e.g. acetyloxy). The chains can be unsubstituted or optionally monosubstituted or disubstituted with hydroxy, N3, CN, SH, amino, halogen (F, Cl, Br, I), aryl of 6 to 12 carbon atoms, alkyl of 1 to 6 carbon atoms , alkoxyalkyl of 2 to 12 carbon atoms, or nitro. The term "alkoxyalkyl" represents an alkoxy group of 1 to 6 carbon atoms, attached to an adjacent alkyl group, from 1 to 6 carbon atoms (for example, methoxymethyl, ethoxymethyl). They may be unsubstituted or optionally monosubstituted or disubstituted with hydroxy, N3, CN, SH, amino, halogen (F, Cl, Br, I), aryl of 6 to 12 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxyalkyl from 2 to 12 carbon atoms or nitro. The term "heterocycle" represents a monocyclic or polycyclic (i.e., bicyclic) ring, saturated or unsaturated, which incorporates one or more heteroatoms (i.e., 1 to 4) selected from N, O, and S. It should be understood that a heterocycle is optionally monosubstituted or disubstituted with OH, SH, amino, halogen, CF3, oxo or alkyl of 1 to 6 carbon atoms. Examples of suitable monocyclic heterocycles include, but are not limited to: pyridine, piperidine, pyrazine, piperazine, pyrimidine, imidazole, thiazole, oxazole, furan, pyran and thiophene. Examples of suitable bicyclic heterocycles include, but are not limited to: indole, benzimidazole, quinoline, isoquinoline, purine and carbazole. The term "aralkyl" represents a substituent comprising an aryl portion of 6 to 10 carbon atoms, fixed by means of an alkyl chain of 1 to 6 carbon atoms (for example, benzyl, phenethyl). The aryl or chain portion of the group is unsubstituted or optionally is monosubstituted or disubstituted with hydroxy, N3, CN, SH, amino, halogen (F, Cl, Br, I), aryl of 6 to 12 carbon atoms, 1 to 6 carbon atoms, alkyloxyalkyl of 2 to 12 carbon atoms or nitro. The term "amino" represents alkyl groups of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms or aralkyl of 7 to 12 carbon atoms. carbon, unsubstituted or optionally monosubstituted or disubstituted with hydroxy, N3, CN, SH, amino, halogen (F, Cl, Br, I), aryl of 6 to 12 carbon atoms, alkyl of 1 to 6 carbon atoms, alkoxyalkyl from 2 to 12 carbon atoms or nitro; where the carbon atoms are covalently bound to an adjacent element, through a nitrogen atom (e.g., pyrrolidine). They include primary, secondary and tertiary amines, and quaternary ammonium salts. The term "protected", when used herein, and unless otherwise defined, refers to a group that is added to an oxygen, nitrogen or phosphorus atom to prevent its further reaction or for other purposes . Those skilled in the art of organic synthesis will know a wide variety of oxygen and nitrogen protecting groups. Suitable protecting groups are described, for example, in Greene and co-authors Protective Groups in Organic Synthesis, John Wiley and Sons, second edition, 1991, which is incorporated herein by way of this reference. By base of pyridine, its derivative or its analogue is meant a base of pyridine found in the nucleoside or an analog thereof, which imitates those bases inasmuch as their structures (the classes of atoms and their arrangement) are similar to the normal bases, but they may possess other additional functional properties or may lack certain functional properties, from the normal bases. Derivatives of such bases or analogs thereof include those that are obtained by replacing a CH portion with a nitrogen atom (e.g., 5-azapyrimidines, such as 5-azacytosine), or may a ring substituted with halogen, hydroxyl, azido , cyano, amino, substituted amino, thiol, alkyl of 1 to 6 carbon atoms and aryl of 6 to 10 carbon atoms.

By the term "pharmaceutically acceptable derivative" of a pyrimidine, is meant any pyrimidine base which may result in the formation of a salt, an ester, acceptable for pharmaceutical use, or a salt of said ester, of a compound of the formula (A), or any other compound which, when administered to a receptor, is capable of providing (directly or indirectly) a compound of the formula (A) or a metabolite or residue thereof, antivirally active. Those skilled in the art will appreciate that the compounds of the formula (A) can be modified to provide their acceptable derivatives for pharmaceutical use, in the functional groups, in the base portion. The compound of the formula (B) can be (B1): or (B2): or a mixture of both enantiomers. The sulfoxide can be a single enantiomer or a mixture of enantiomers, including, but not limited to, a racemic mixture. The coupling step of the process forming the object of the present invention includes the addition of one or more elements of group IB or IIB. The element, or the combination of elements, used, may be in its oxidized state. This element or this combination of elements of group IB or IIB, catalyzes the coupling step. The selected element, or the combination of elements of group IB or group IIB, are present in amounts of between about 0.25 mole percent and 100 mole percent. In another embodiment, the concentration of the element or the combination of group IB or group IIB elements may be between about 5 percent and about 35 percent. The process forming the object of the present invention includes a coupling step, in which the element or the combination of group IB or group IIB elements are selected from the group comprising Cu +, Cu2 +, Ag +, Au +, Au3 +, Zn2 + , Cd2 + and combinations of them. The process forming the object of the present invention includes a coupling step, wherein the element or combination of group IB or group IIB elements are selected from Cu +, Cu2 + or Zn2 +. The term "tertiary amine" includes tertiary amines with high basicity. The tertiary amine has the form N (Z4) (Z5) (Z6), wherein (Z4), (Z5), (Z6) are independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, optionally substituted with alkyl of 1 to 3 carbon atoms, aryl of 6 to 10 carbon atoms, halogen. Examples of the tertiary amine include: triethylamine, diethylcyclohexylamine, diethylmethylamine, dimethylethylamine, dimethylisopropylamine, dimethylbutylamine, dimethylcyclohexylamine, tributylamine, diethylmethylamine, dimethylisopropylamine and diisopropylethylamine. The amount of tertiary amine may vary from about one equivalent to about four equivalents. The amount of tertiary amine used can vary between about one equivalent and two equivalents. The coupling step of the process forming the object of the present invention is carried out in a suitable coupling solvent. A suitable coupling solvent includes chlorinated organic solvents of 1 to 10 carbon atoms. Suitable coupling solvents also include: chloroalkons of 1 to 8 carbon atoms, chloroalkenyl of 1 to 8 carbon atoms, chloroaryl of 6 to 10 carbon atoms, alkyl nitriles of 1 to 8 carbon atoms, and combinations thereof. It is possible to select the coupling solvents of: chloromethanes, chloroethanes, methanonitriles, or their mixtures. Coupling solvents of interest include: dichloromethane, chloroform, acetonitrile, dichloroethane, chlorobenzene and combinations thereof. The amount of coupling solvent used can vary between about 5 mL per gram of sulfoxide and 50 mL per gram of sulfoxide. In an alternative embodiment of the invention the amount of coupling solvent is between 10 mL per gram of sulfoxide and 30 mL per gram of sulfoxide. The coupling step of the process forming the object of the present invention is affected by the temperature of the reaction. The cis to trans ratio of the product of the formula (D) is inversely proportional to the temperature of the reaction. The coupling step is carried out at a temperature between about 40 degrees C and about -40 ° C. In an alternative modality, the reaction temperature of the coupling step is between about 30 ° C and about -50 ° C. The second step in the process forming the object of the present invention is a deprotection step. The crystallization step with deprotection is carried out in a suitable solvent. Particularly interesting are the solvents which favor the crystallization of the product of the formula (A). Suitable solvents include: water, methanol, ethanol, toluene, tert-butyl methyl ether, or combinations thereof. Deprotection may also include the presence of adequate amounts of a deprotection agent. Of particular interest are the deprotection agents that assist in the separation of the cis product from the formula (A). Suitable deprotection agents are selected according to the identity of the protecting group in the intermediate of formula (D) as shown in Greene and coauthors: Protective Groups in Organic Synthesis, John Wiley and Sons, second edition, 1991.

The deprotection agents can be alkaline. Deprotection agents include: sodium hydroxide, sodium methoxide, ammonium hydroxide, potassium hydroxide, lithium hydroxide and methanolic ammonia. In another embodiment of the present invention, the deprotection agent is present in catalytic amounts. In another embodiment, the deprotection agent is present in concentrations ranging from about 0.1 mole percent to about 50 mole percent. An alternative embodiment includes concentrations of the deprotection agent ranging from about 5 mole percent to about 20 mole percent of the deprotection agent. Conveniently, the base R1 is selected from: wherein: x is oxygen, NH or sulfur; and it is oxygen, NH or sulfur; R8 and R9 are independently selected from hydrogen, hydroxyl, amino, alkyl of 1 to 6 carbon atoms or alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, acyl of 1 to 10 carbon atoms, aryl from 6 to 10 carbon atoms, carbonylarnyl of 6 to 11 carbon atoms, carbonyl oxyalkyl of 1 to 7 carbon atoms, carbonyloxyaryl of 6 to 11 carbon atoms, carbonylaminoalkyl of 2 to 7 carbon atoms, or amino acids; R8 can be a carbocyclic ring of 3 to 8 carbon atoms, saturated or unsaturated, optionally substituted with COOH, C (0) NH2, OH, SH, NH2, N02, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halogen, C (0) R 14, where R 14 is an alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms of carbon; and R9 is selected from H, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms and alkynyl of 2 to 6 carbon atoms; R8R9 may also be connected to the nitrogen atom to form a saturated or unsaturated heterocyclic ring, of 3 to 8 carbon atoms, optionally substituted with C (0) OH, C (0) NH2, OH, SH, NH2, N02, alkyl from 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halogen, C (0) R 14, where R 14 is an alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms and C (0) 0R15, wherein R15 is an alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms carbon; R10 R11, R12 and R13 are each independently selected from hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, carbamoyl, alkoxycarbonyl of 2 to 7 carbon atoms, hydroxymethyl, trifluoromethyl, arylthio of 6 to 10 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, substituted or unsubstituted by halogen or azido, alkynyl of 2 to 6 carbon atoms, acyloxy of 1 to 6 carbon atoms, thiocarboxy, thiocarbamoyl, carbamate , ureido, amidino or aryloxy of 6 to 10 carbon atoms. In another embodiment of the present invention, R1 is: (SAW) wherein R8 and R9 are independently selected from hydrogen, hydroxyl, amino, alkyl of 1 to 10 carbon atoms or alkenyl of 2 to 10 carbon atoms, alkynyl of 2 to 10 carbon atoms, acyl of 1 to 10 carbon atoms, aryl of 6 to 10 carbon atoms, carbonylarnyl of 6 to 16 carbon atoms, carbonyloxyalkyl of 1 to 10 carbon atoms, carbonyloxyaryl of 6 to 16 carbon atoms, carbonylaminoalkyl of 2 to 12 carbon atoms, or amino acids; R10 and R11 are each independently selected from hydrogen, halogen, hydroxyl, hydroxymethyl, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, substituted or unsubstituted with halogen, azido, alkynyl from 2 to 6 carbon atoms, or aryloxy of 6 to 10 carbon atoms; and X and Y are independently selected from O or S. In an alternative embodiment, R1 is a pyrimidine base, selected from N-alkylpyrimidines, N4-acylpyrimidine, 4-halopyrimidine, N4-acetylenic pyrimidines, 4-amino and N4-acylpyrimidine, 4-hydroxyalkylpyrimidine, 4-thioalkylpyrimidine, thymine, cytosine, 6-azapyrimidine, including 6-azacytosine, 2- and / or 4- mercaptopyrimidine, uracil, C5-alkylpyrimidines, C5-benzylpyrimidine, C5-halopyrimidine, C-vinylpyrimidine, C5-acetylenic pyrimidine, C5-acylpyrimidine, C5-amidopyrimidine, C5-cyanopyrimidine, C5-nitropyrimidine, C5-aminopyrimidine, 5-azacytidinyl , 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl or pyrazolopyrimidinyl. The functional oxygen and nitrogen groups, in R1, can be protected when necessary or convenient. Suitable protecting groups are well known to those skilled in the art, and include: trimethylsilyl, dimethylhexylsilyl, tert-butyldimethylsilyl and tert-butyldiphenylsilyl, trityl, alkyl groups of 1 to 12 carbon atoms, acyl groups of 1 to 12 carbon atoms, such as acetyl and propionyl, benzoyl, methanesulfonyl and p-toluenesulfonyl. In a further embodiment of the present invention, R1 is selected from: cytosine, uracil, thymine, 5-fluoropyrimidine or protected analogs of those bases. Another embodiment of the present invention includes a stereoselective process for forming predominantly cis-nucleosides or analogs and nucleoside derivatives of the formula (A): wherein: R1 is a pyrimidine base, selected from N4-alkylpyrimidines, N4-acylpyrimidine, 4-halopyrimidine, N4-acetylenic pyrimidines, 4-amino and N4-acylpyrimidine, 4-hydroxyalkylpyrimidine, 4-thioalkylpyrimidines, thymine, cytosine, 6-azapyrimidine, including 6-azacytosine, 2- and / or 4-mercaptopyrimidine, uracil, C5-alkylfirimidine, C5-benzylpyrimidines, C5-halopyrimidines, C5-vinylpyrimidine, C5-acetylenic pyrimidine, C5-acylpyrimidine, C5 amidopyrimidine, C5-cyanopyrimidine, C5-nitropyrimidine, C5-aminopyrimidine, 5-azacytidinyl, 5-azauracylyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl or a pharmaceutically acceptable derivative thereof; and Q is oxygen; which consists of the step of coupling a compound of the formula (B): wherein: R2 is aralalkyl of 7 to 10 carbon atoms, acyl of 1 to 16 carbon atoms or Si (Z1) (Z2) (Z3), wherein Z1, Z2 and Z3 are independently selected from the group consisting of hydrogen , alkyl of 1 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine, iodine, alkoxy of 1 to 6 carbon atoms or aryloxy of 6 to 20 carbon atoms; aralkyl of 7 to 20 carbon atoms, optionally substituted with halogen, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; aryl of 6 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine, iodine, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; tria Iq u ilsi I ilo, fluorine, bromine, chlorine and iodine; with a base R1, as defined above, in a suitable coupling solvent, in the presence of a catalytic amount of an element, or of a combination of elements of group IB or group IIB; a tertiary amine or a Lewis acid of the formula (C): R4 R7 - Si - R5 I R6 (C) wherein: R4, R5 and R6 are independently selected from the group consisting of hydrogen; alkyl of 1 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine, iodine, alkoxy of 1 to 6 carbon atoms or aryloxy of 6 to 20 carbon atoms; aralkyl of 7 to 20 carbon atoms, optionally substituted with halogen, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; aryl of 6 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine, iodine, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; trialkylsilyl; fluorine; bromine; chlorine and iodine; and R7 is selected from the group consisting of fluorine; bromine; chlorine; iodo; sulfonate esters of 1 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine or iodine; alkyl esters of 1 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine or iodine; triiodide; a silyl group of the general formula (R4) (R5) (R6) Si (where R4, R4 and R6 are as defined hereinabove); arylselenenyl of 6 to 20 carbon atoms; arylsulfenyl of 6 to 20 carbon atoms; alkoxyalkyl of 6 to 20 carbon atoms; and trialkylsiloxy; to produce an intermediate of the formula (D): wherein Q, R1 and R2 are as defined hereinabove. The coupling step is followed by a deprotection step, in which the intermediate (D) is dissolved in a suitable solvent, in the presence of appropriate amounts of a deprotection agent, to produce the cis-nucleosides or analogues or nucleoside derivatives of the formula (A). The present invention includes the embodiment in which the stereoselective process of forming predominantly cis-nucleosides or analogs and nucleoside derivatives of the formula (A): wherein: R1 is a pyrimidine base, selected from cytosine, uracil, thymine, 5-fluoropyrimidine, or a derivative thereof, acceptable for pharmaceutical use; and Q is oxygen; which consists of the step of coupling a compound of the formula (B): wherein: R2 is: where W is halogen, alkyl of 1 to 16 carbon atoms, alkoxyalkyl of 2 to 16 carbon atoms, aryl of 6 to 10 carbon atoms, alkoxy of 1 to 16 carbon atoms or nitro; or where E is aryl of 6 to 10 carbon atoms, alkoxy of 1 to carbon atoms, alkoxyalkyl of 2 to 16 carbon atoms, alkyl of 1 to 16 carbon atoms; or Si (Z1) (Z2) (Z3), where independently selected from the group consisting of hydrogen, alkyl of 1 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine, iodine; aralalkyl of 7 to 10 carbon atoms, substituted with fluorine, bromine, chlorine or iodine; and aryl of 6 to 10 carbon atoms, optionally substituted with fluorine, bromine, chlorine or iodine; with a base R1, as defined hereinabove, in a suitable coupling solvent, in the presence of a catalytic amount of Cu or Zn, or mixtures thereof; a tertiary amine and a Lewis acid, selected from trimethylsilyl triflate, bromotrimethylsilane or iodotrimethylsilane; to produce an intermediate of the formula (D): wherein Q, R1 and R2 are as previously defined. The coupling step is followed by a deprotection step, in which the intermediate (D) is dissolved in a suitable solvent, in the presence of appropriate amounts of a deprotection agent to produce the cis-nucleosides or the nucleoside analogs or derivatives of the formula (A). The process that constitutes the objective of the present invention includes the reaction scheme shown in scheme 1: SCHEME 1 cis / trans nucleoside protected unprotected cis-nucleoside The various steps illustrated in scheme 1 can be briefly described as follows: Step 1: The sulfoxide of formula (B) can be obtained using various methods, including those described in the publications of TCP WO 92/08717 and WO 96/29176; in J. Med. Chem., 38 (1) 1-4 (1995); Tetrahedron Lett., 35 (27, 4739-4742 (1994), Bioorg, Med. Chem. Lett., 3 (8) 1723-1728 (1993) and Eur. J. Org. Chem., 6: 1455-1458 ( 1999. The sulfoxide can be a single enantiomer or a mixture of enantiomers, including, but not limited to, a racemic mixture.The sulfoxide of the formula (B) is coupled to the base R. The base R1 can be previously protected , for example, it can be a silylated pyrimidine base (or silylated in situ), or a pharmaceutically acceptable derivative can be used.The coupling reaction takes place in the presence of a tertiary amine, a Lewis acid of the formula ( C) and catalytic amounts of an element of groups IB or IIB, in a suitable coupling solvent, to give the cis / trans-pyrimidine nucleoside of the formula (D) In the resulting intermediate of the formula (D), the cis isomer predominates over the trans isomer, in a ratio equal to or greater than 2 to 1. The ratio of cis to trans isomer is inver proportional to the reaction temperature. The coupling reaction can be carried out at or below room temperature. The temperature of the coupling step can be between about 0 ° C and about -50 ° C. If a silylated base is used, the suitable silylating agent can include: tert-butyldimethylsilyl triflate, 1,1,1,3,3,3-hexamethyldisilazane, TMSI, N, 0, bis (TMS) acetonide and trimethylsilyl triflate. Additional protective agents are described in Greene and co-authors, Protective Groups in Organic Synthesis, John Wiley and Sons, second edition, 1991. The tertiary amine used in step 1 includes: triethylamine, diethylcyclohexylamine, diethylmethylamine, dimethylethylamine, dimethylisopropylamine, dimethylbutylamine, dimethylcyclohexylamine, tributylamine, diethylmethylamine, dimethylisopropylamine and diisopropylethylamine, and combinations thereof. The element, or combination of elements, of groups IB or IIB, used in step 1, include: Cu, Ag, Au, Zn or Cd, in the oxidized state. The suitable coupling solvent is an organic solvent having from one to ten carbon atoms. Suitable coupling solvents include: methylene chloride, acetonitrile and mixtures thereof. Suitable Lewis acids include: trimethylsilyl triflate, bromotrimethylsilane, iodotrimethylsilane and combinations thereof. The amount of Lewis acid may be between about 2 equivalents and about 5 equivalents. Step 2: The cis / trans-pyrimidine-1,3-oxathiolane nucleoside of the formula (D) is dissolved in a suitable deprotection solvent, in the presence of suitable amounts of a deprotection agent, to produce the cis-nucleosides or the like or nucleoside derivatives of the formula (A). The deprotection step is carried out at a temperature below the boiling point of the appropriate deprotection solvent. The reaction temperature of the deprotection step can be between -30 ° C and 60 ° C. The reaction can be carried out at a temperature between 0 ° C and 35 ° C. A suitable deprotection solvent promotes the crystallization of the product of the formula (A). Suitable solvents include: water, methanol, ethanol, toluene, tert-butyl methyl ether, or combinations thereof. Suitable deprotection agents include: sodium idroxide, sodium methoxide, ammonium hydroxide, potassium hydroxide, lithium hydroxide and methanolic ammonia. Of particular interest are the deprotection agents which assist in the separation of the product of the formula (A).

SCHEME 1a cis / trans-nucleoside cis-nucleoside The various steps illustrated in scheme 1a can be briefly described as follows: Step 1: The 1,3-oxathiolane sulfoxide of the formula (Bx) can be obtained using various methods, including those that are described in the publications of TCP WO 92/08717 and WO 95/29176; in J. Med. Chem., 38 (1) 1-4 (1995), Tetrahedron Lett., 35 (27) 4739-4742 (1994); Bioorg. Med. Chem. Lett., 3 (8) 1723-1728 (1993). The asymmetric synthesis of the sulfoxide of the formula (Bx) is described by Caputo and co-authors in Eur. J. Org. Chem., 6: 1455-1458 (1999). The 1,3-oxathiolane sulfoxide of the formula (Bx) is coupled to the base R1. The base R1 may be pre-protected, for example, it may be a silylated pyrimidine base (or it may be silylated in situ), or a pharmaceutically acceptable derivative. The coupling reaction is carried out in the presence of a tertiary amine, a Lewis acid of the formula (C) and a catalytic amount of an element of the groups IB or IIB, in a suitable coupling solvent, to give the cis / nucleoside trans-pyrimidin-1,3-oxathiolane of the formula (Dx). In the intermediate resulting from formula (Dx) the cis isomer on the trans isomer predominates, in a ratio equal to or greater than 2 to 1. The ratio of cis to trans isomer is inversely proportional to the temperature of the reaction. The reaction can be carried out at or below room temperature. The silylating agent that can be used for the protection of R1 includes tert-butyldimethylsilyl triflate, 1,1,1,3,3,3-hexamethyldisilazane, T SI, N, 0, bis-TMS-acetonide and trimethylsilyl triflate. The tertiary amine used in step 1 includes: triethylamine, diethylcyclohexylamine, diethylmethylamine, dimethylethylamine, dlmethylisopropylamine, dimethylbutylamine, dimethylcyclohexylamine, tributylamine, diethylmethylamine, dimethylisopropylamine and diisopropylethylamine, and combinations thereof.

The element, or combination of elements of groups IB or IIB used in step 1 include: Cu, Ag, Au, Zn or Cd, in the oxidized state. The suitable coupling solvent is an organic solvent. Suitable coupling solvents include: methylene chloride, acetonitrile or mixtures thereof. The Lewis acid which can be used in this step includes: tri-methyl triflate Is i I i, bromotrimethylsilane, iodotrimethylsilane and mixtures thereof. The amount of Lewis acid may be between about 2 equivalents and about 5 equivalents. Step 2: The cis / trans-pyrimidine nucleoside of the formula (Dx) is dissolved in a suitable deprotection solvent, in the presence of suitable amounts of a deprotection agent, to give the cis-nucleosides or the analogues or nucleoside derivatives of the formula (Ax). A suitable deprotection solvent promotes the crystallization of the product of the formula (A). Suitable solvents include: water, methanol, ethanol, toluene, tert-butyl methyl ether, or combinations thereof. Suitable combinations of solvents include: mixtures of methanol and water, methanol and toluene, methanol and tert-butyl methyl ether. Suitable deprotection agents include: sodium hydroxide, sodium methoxide, ammonium hydroxide, potassium hydroxide, lithium hydroxide and methanol ammonia. Particularly interesting are the deprotection agents that assist in the separation of the product of the formula (A). The deprotection step is carried out at a temperature below the boiling point of the appropriate deprotection solvent. The following examples illustrate the present invention in a manner in which it can be put into practice; but as such, they should not be considered as limitations to the scope of the processes of the present invention. 1) 2-BENZOILOXI ETIL-1.3-OXAT1QLANO The compound (1) was dissolved in toluene, and the solution was heated to 90-100 ° C. Catalyst was added, followed by mercaptoethanol (in portions). 5 mole percent catalyst was used. The reactions were carried out on a 15 g scale, at a concentration of 0.3 M (1). The reaction mixture was allowed to reflux, with water separation by a Dean-Stark trap. The results for this step are shown in Table 1.

TABLE 1 Compound (2) was identified by NMR with H and with 13C Rf: 0.39 (hexane: ethyl acetate). NMR with 1H: d (ppm in CDCl 3): 8.03 (m, 2H, aromatic) 7.53 (m, 1H, aromatic) 7.39 (m, 2H, aromatic) 5.41 (dd, 1H, C2-H) 4.43 (m, 2H , C2-CH2OCC6H5) 4.21 (m, 1H, Ce-H) 3.96 (m, 1H, C5-H) 2.98 (m, 2H, C4-H). NMR with 13 C d (ppm in CDCl 3): 166.82, 133.74, 130.35, 128.97, 83.58, 71.87, 66.62 and 32. 74 2) S-OXIDE OF 2-BENZ01LOXIMETIL-1.3-OXATIOLANO 46 mL (0.44 mol) of 30 percent cold hydrogen peroxide was added to 82 g (0.366 mol) of (2) in 8 mL of toluene. 4.5 mL (0.044 mol, 10 mole percent) of 10 M sulfuric acid was added dropwise (addition time, approximately 1 minute). The reaction mixture was stirred vigorously at 25-30 ° C for two hours, and then one hour at 30 ° C. 100 mL of water was added, followed by 3.7 g (0.044 mol) of sodium bicarbonate, followed by 8 g of sodium metabisulfite. The organic layer was separated and the aqueous phase was extracted with 3 x 20 mL of dichloromethane. The combined extracts were dried over sodium sulfite, concentrated to dryness and triturated with hexane to form 83 g of a solid. 94 percent of the compound (3) sought was obtained; p. F. 70-72 °. 1 H NMR: d (ppm in CDCl 3): 8.05 (m, 2H, aromatic, cis-isomer) 7.95 (m, 2H, aromatic, trans isomer) 7.56 (m, aromatic) 7.23 (m, aromatic) 4.77 (m, 4H , C2-H, C5-H and C2-CH2OOCC6H5) 4.43 (m, 1H, C5-H, trans isomer) 4.09 (m, 1H, C5-H, cis-isomer) 3.11 (m, 2H, C4-H, isomer trans) 2.75 (m, 2H, C4-H, cis-isomer, 13 C-NMR: d (ppm in CDCl 3): cis-isomer: 166.64, 134.02, 130.42, 129.88, 129.06, 96.16, 68.83, 59.47 and 54.30 trans isomer: 166.36, 134.12, 130.29, 129.68, 129.15, 108.07, 70.09, 61.83 and 53.47 3) (±) -CIS.TRANS-2-BENZOYLEMETIL-4- (N-ACETYLCYTOSIN-1'-IL¾-1,3-OXATIOLAN Compound (3) was dissolved in 20 mL / g methylene chloride and cooled to -15 ° C. Between 1 and 2 equivalents of the amine was added, followed by the addition of between 2 and 5 equivalents of TMSI, while maintaining the internal temperature below -5 ° C. It was stirred at -5 ° C to -10 ° C, until the compound (3) disappeared. 20% CuCI and 1.1 equivalents of pyrimidine were added. The reaction mixture was heated and maintained at 5-10 ° C until the TLC indicated that the reaction was complete. The reaction mixture was poured into 5 percent NH4OH and stirred for ten minutes, until no solid precipitate was detected. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The organic layer was washed with water, with 2 percent HCl and with dilute Na2S203. The washed organic layer was evaporated to give the product, compound (4). The results of this step are shown in Table 2. They were characterized by R N with 1H and with 13C. cis isomer: NMR with 1H: d (ppm in CDCl 3) 9.61 (b, 1H, C4-NHCOCH 3) 8.29 (d, 1H, Ce ~ H) 8.06 (m, 2H, aromatic) 7.65 (m, 1H, aromatic) 7.51 (m, 2H, aromatic) 7.25 (d, 1H, C5-H) 6.61 (d, 1H, C4-H) 5.50 (t, 1H, C2-H) 4.80 (m, 2H, C2-CH2OOCC6H5) 4.48 (d , 1H, C5-H) 4.05 (dd, 1H, Cs-H) 2.25 (s, 3H, CH3). 13 C NMR: d (ppm in CDCl 3) 170.93, 166.28, 162.80, 155.76, 146.06, 133.91, 129.90 128.84, 97.45, 85.88, 78.25, 64.60, 63.53 and 24.71. trans isomer: NMR with 1H: d (ppm in D SO d6): 10.88 (s, 1H, C4-NHCOCH3) 8.13 (d, 1H, C6-H) 7.96 (m, 2H, aromatic) 7.68 (m, 1H, aromatic) 7.52 (m, 2H, aromatic) 7.20 (d, 1H, C5-H) 6.35 (d, 1H, C4-H) 5.96 (dd, 1H, C2-H) 4.58 (dd, 1H, C2-CH2OOCC6H5) 4.44 (d, 1H, C5-H) 4.29 (m, 2H, C5-H and CH2OOCC6H5) 2.07 (s, 3H, CH3) NMR with 13C: d (ppm in DMSO d6): 171.53, 165.84, 162.76, 155.21, 146.59, 134.00, 129.64 129.23, 96.54, 83.78, 74.24, 64.58, 64.01 and 24.35.

TABLE 2 Pyrimidine Catalyst Base Conditions Rendim. Cis / trans Rendim. (molar eq.) (cis-trans)% cis N-Ac-Cy DIPEA. C¾Cl2r -15 * C 80% 2.0: 1 53 l.leq 1.2eq RT, O / H H-Ac-Cy DIPEft. CuCl 3 CH 2 Clíf -15 ° C, 91% 3.9: 1 72 l.leq 1.2eq (20%) 3h RT, O / S K-Ac-C TEA CaCl 2 C¾Cl_., -15 ° C. 75% 3.8 i 1 59 l.leg 1.2eq (20%) 5h RT, O / H K-Ac-Cy DMCA CuClj CHaCli, -15 ° C, 80% 3.4: 1 62 l.leg 1.2eq. { twenty%} Sil RT, O / H N-Ac-Cy DSCA CuCl2 a¾? ¾, -15"C 71% 3.9: 1 57 l.leq 1.2eq (20%) RT, O / S H-Ac-Cy DIPEA CttCl2 (2 %) CH2Cl2, -15 ° C, 80% 2.4: 1 56 l.leq 1.2eq 3b RT, O / H ar-Ac-C DIPEA CuBri CEjClj, -15 ° C, 80% 3.7 i 1 63 l.leq 1.2 eq <; 2Q% > 5h RT, O / K H-Ac-Cy DIPEA Cu (acac) to C¾Cl2f -15 eC, 85% 3.7: X 67 l.leq 1.2eq (20%) 5fa RT, O / K N-Ac-Cy DIPKA CttCl (20%) CHjCla, -15 ° C, 80% 3.6 Í X 63 l.leq í.2eq 5h RT, O / S H-Ac-Cy DIPEA cul (20%) C¾CI2, -15 eC, 74% 3.5 il 58 l.leq l "2eq Sh RT, O / S? -? P-Cy DIPEA CuSCS C¾C12, -15 ° C, 70% 3.1íl 53 l.leq 1.2eq (20%) 5h RT, O / H N- Ac-Cy DIPEA ZaBx ¿CH2C13, -15 eC, 53% 3.1: 1 40 l.leq 1.2eq (20%) 51 »RT, O / HC DIPEA CBC12 CHZC12, -i5 &C, 72% 2-4.1 51 l.leg l - 2eq (20% i 5fe RT, O / H Cy = cytosine D I P EA = d iisopropylethylamine TEA = triethyl lam N D ECA = diethylcyclohexy lamin D MCA = d imethyl cyclohexy lam ina Cu (acac) 2 = copper acetylacetonate (II) 4) 2-HYDROXIMETlL-4- (ClTOSlN-1'-IL) -1,3-OXATIOLAN A suspension of the substrate, sodium methoxide, 10 mole percent, and the appropriate solvent was stirred at room temperature for two hours before being filtered. The filter cake was dried and weighed, before checking the C / T ratio (by NMR with H) and the yield. The results of this step are shown in table 3.

TABLE 3 = room temperature ) SYNTHESIS OF 2-BENZOlLMETIL-4- (N-ACETYLCYTOSIN-1 1.3-OXATIOLAN USING S-OXIDE OF (-) OR (÷) -2- BENZOYLOXY ETHYL-1,3-OXATIOLAN The enantiomerically pure compound (3a) was dissolved in 10 mL / g of methylene chloride and cooled to the reaction temperature. The amine was added, followed by the addition of TMSl, while maintaining the internal temperature below -5 ° C. It was stirred at -5 ° C to -40 ° C until the compound (3a) disappeared. CuCl (20 percent) and 1.1 equivalents of pyrimidine were added. The reaction mixture was heated and maintained between -40 and 30 ° C until the TLC indicated that the reaction was complete. The reaction was cooled to 0 ° C-5 ° C. 12 g of Celite (100 weight percent / weight) was added to the suspension and stirred. Concentrated ammonium hydroxide was slowly added and the temperature of the suspension maintained between 0 ° C and 10 ° C. It was stirred at 0 ° C-5 ° C. The suspension was filtered and the cake resuspended in dichloromethane. It was stirred and then filtered. The phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic layers were washed with a 2 percent solution of ammonium hydroxide, with water, with 2 percent hydrochloric acid solution, with 2 percent sodium metabisulfite solution and with saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate, filtered, then reduced in volume in vacuo to give a crude material, coupled to the base, as a crude colored solid. The solids were dissolved in ethyl acetate and allowed to crystallize. The suspension was stirred at 0-5 ° C and then filtered. The solids were dried in vacuo to give the pure product, coupled to the base, as a pale crude solid. The results of this step are shown in Table 4 and Table 5. 1 H NMR (300 MHz) (CDCl 3) d 2.27 (s, 3 H, CH 3 cis), 2. 29 (s, 3H, CH3 trans), 4.06 (dd, J = 4.5 Hz and J = 10.8 Hz, 1H, C5 cis), 4.30 (dd, J = 3.4 Hz and J = 12.4 Hz, 1H, C5 trans), 4.49 (dd, J = 3.1 Hz and J = 10.8 Hz, 1H, C5 cis), 4.72 (dd, J = 8.3 Hz and J = 12.4 Hz, 1H, C5 trans), 4.77 (AB, J = 4.5 Hz, 2H , CH2OBz, cis), 4.84 (AB, J = 2.3 Hz, 2H, CH2OBz, trans), 5.50 (dd, J = 3.1 Hz and J = 4.5 Hz, 1H, C4, cis), 5.92 (dd, J = 3.4 Hz and J = 8.3 Hz, 1H, C4, trans), 6.61 (dd, J = 2.3 Hz, trans and J = 4.5 Hz, cis, 1H, C2), 7.25 (d, J = 7.5 Hz, 1H, C5 ' ), 7.5-8.1 (m, 10H, cis and trans aromatics), 8.30 (d, J = 7.5 Hz, 1H, C6 '), 9.50 (s, 1H, NH). NMR with 13 C (300 MHz) (CDCl 3) d 25.9 (cis and trans), 64.3 (cis), 65.1 (trans), 65.3 (cis and trans), 76.1 (trans), 78.7 (cis), 84.7 (trans), 86.2 (cis), 97.9 (cis), 98.1 (trans), 128.6 (cis and trans), 128.7 (cis and trans), 129.2 (cis and trans), 129.4 (cis and trans), 129.8 (cis and trans), 133.5 (trans), 133.7 (cis), 145.3 (trans), 145.6 (cis) , 155.2 (trans), 155.3 (cis), 162.5 (cis and trans), 162.6 (trans), 165.7 (cis), .0 (cis), 171.1 (trans). TABLE 4 TABLE 5 TEA = triethylamine DIPEA = diisopropylethylamine DMCA = dimethylcyclohexylamine (i-pro) NMe2 = isopropyldimethylamine

Claims

CLAIMS 1. - A stereoselective process for forming predominantly cis nucleosides or nucleoside analogs and derivatives of the formula (A): wherein: R1 is a pyrimidine base or a derivative thereof, acceptable for pharmaceutical use; and Q is carbon, oxygen or sulfur; which consists of the coupling step of a compound of the formula (B): wherein: R2 is aralalkyl of 7 to 10 carbon atoms, acyl of 1 to 16 carbon atoms or Si (Z1) (Z2) (Z3), wherein Z Z2 and Z3 are independently selected from the group consisting of hydrogen; alkyl of 1 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine, iodine, alkoxy of 1 to 6 carbon atoms or aryloxy of 6 to 20 carbon atoms; aralkyl of 7 to 20 carbon atoms, optionally substituted with halogen, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; aryl of 6 to 20 carbon atoms substituted with fluorine, bromine, chlorine, iodine, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; trialkylsilyl; fluorine; bromine; chlorine and iodine; with a base R1; wherein R1 is a pyrimidine base, or a derivative thereof acceptable for pharmaceutical use; in a coupling solvent, in the presence of a catalytic amount of an element or a combination of elements of group IB or IIB of the Periodic Table; a tertiary amine and a Lewis acid, to produce an intermediate of the formula (D): wherein R1, R2 and Q are as defined above; and a second step to deprotect the intermediate of the formula (D), to produce the cis-nucleosides or analogues or nucleoside derivatives of the formula (A). 2. A process according to claim 1, further characterized in that the Lewis acid is a compound of the formula (C): R4 R7-Si-R5 R6 (C) wherein: R4, R5 and R6 are selected independently of the group consisting of hydrogen; alkyl of 1 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine, iodine, alkoxy of 1 to 6 carbon atoms or aryloxy of 6 to 20 carbon atoms; aralkyl of 7 to 20 carbon atoms, optionally substituted with halogen, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 atoms. of carbon; aryl of 6 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine, iodine, alkyl of 1 to 20 carbon atoms or alkoxy of 1 to 20 carbon atoms; trialkylsilyl; fluorine; bromine; chlorine and iodine; and R7 is selected from the group consisting of fluorine; bromine; chlorine; iodo; sulfonate esters of 1 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine or iodine; alkyl esters of 1 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine or iodine; triiodide; a silyl group of the general formula (R4) (R5) (R6) Si (where R4..R5 and R6 are as defined hereinabove); arylselenenyl of 6 to 20 carbon atoms; arylsulfenyl of 6 to 20 carbon atoms; alkoxyalkyl of 6 to 20 carbon atoms; and trialkylsiloxy 3.- A conformance process, with claim 1, further characterized in that R1 is selected from: (v) (i) (vil) (viii) where: X is oxygen, NH or sulfur; And it's oxygen, NH or sulfur; R8 and R9 are independently selected from hydrogen, hydroxyl, amino, alkyl of 1 to 6 carbon atoms or alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, acyl of 1 to 10 carbon atoms, aryl from 6 to 10 carbon atoms, carbonylarnyl of 6 to 11 carbon atoms, carbonyloxyalkyl of 1 to 7 carbon atoms, carbonyloxyaryl of 6 to 11 carbon atoms, carbonylaminoalkyl of 2 to 7 carbon atoms, or amino acids; R8 can be a saturated or unsaturated carbocyclic ring, of 3 to 8 carbon atoms, optionally substituted with COOH, C (0) NH2, OH, SH, NH2, N02, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halogen, C (0) R 14, where R 14 is an alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 atoms carbon and C (0) OR15, where R15 is an alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms; and R9 is selected from H, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms and alkynyl of 2 to 6 carbon atoms: R8R9 can also be connected to the nitrogen atom to form a saturated heterocyclic ring or unsaturated, of 3 to 8 carbon atoms, optionally substituted with C (0) OH, C (0) NH2, OH, SH, NH2, N02, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms, halogen, C (0) R 14, where R 14 is an alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms and C (0) OR15, where R15 is an alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, alkynyl of 2 to 6 carbon atoms; and R10, R11, R12 and R13, are each independently selected from: hydrogen, halogen, hydroxyl, amino, cyano, carboxyl, carbamoyl, alkoxycarbonyl of 2 to 7 carbon atoms, hydroxymethyl, trifluoromethyl, arylthio of 6 to 10. carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, substituted or unsubstituted by halogen or azido, alkynyl of 2 to 6 carbon atoms, acyloxy of 1 to 6 carbon atoms, thiocarboxy , thiocarbamoyl, carbamate, ureido, amidino or aryloxy of 6 to 10 carbon atoms. 4. - A process according to claim 1, further characterized in that the element or combination of elements of groups IB or IIB is Cu, Ag, Au, Zn or Cd. 5. - A process according to claim 1, characterized also because the tertiary amine has the form N (Z4) (Z5) (Z6), wherein (Z4), (Z5), (Z6) are independently selected from the group consisting of alkyl of 1 to 6 carbon atoms, optionally substituted with alkyl of 1 to 3 carbon atoms, 6 to 10 carbon atoms, or halogen. 6. A process according to claim 1, further characterized in that the organic solvent is a chloroalkyl of 1 to 8 carbon atoms, chloroalkenyl of 1 to 8 carbon atoms, a chloroaryl of 6 to 10 carbon atoms, alkyl nitrile of 1 to 6 carbon atoms, or mixtures thereof. 7. A process according to claim 6, further characterized in that the organic solvent is selected from the group consisting of chloromethanes, chloroethanes, methanonitriles and mixtures thereof. 8. A process according to claim 5, further characterized in that the tertiary amine is triethylamine, diethylcyclohexylamine, diethylmethylamine, dimethylethylamine, dimethyl-isopropylamine, dimethylbutylamine, dimethylcyclohexylamine, tributylamine, diethylmethylamine, dimethylisopropylamine, diisopropyl-ethylamine or combinations thereof. 9. A process according to claim 4, further characterized in that the element or combination of elements of groups IB or IIB is Cu, Zn or combinations thereof. 10. A process according to claim 1, further characterized in that Q is oxygen. 11. A process according to claim 1, further characterized in that the coupling step is carried out at a temperature equal to or less than 30 ° Celsius. 12. - A process according to claim 1, further characterized in that the step of deprotection is carried out in the presence of a deprotection agent and a deprotection solvent, which favors the crystallization of the cis-nucleosides or the analogues or derivatives of nucleoside of the formula (A). 13. - A process according to claim 12, further characterized in that the deprotection agent is alkaline. 14. - A process according to claim 13, further characterized in that the deprotection agent is sodium hydroxide, sodium methoxide, ammonium hydroxide, potassium hydroxide, lithium hydroxide, methanolic ammonia or combinations thereof. 15. - A process according to claim 12, further characterized in that the deprotection solvent is water, methanol, ethanol, toluene, tert-butyl methyl ether or combinations thereof. 16. A process according to claim 3, further characterized in that 1 is selected from N4-alkylpyrimidines, N4-acylpyrimidines, 4-halopyrimidines, N -acetylenic pyrimidines, 4-amino and N4-acylpyrimidines, 4- hydroxyalkylpyrimidines, 4- thioalkylpyrimidines, thymine, cytosine, 6-azapyrimidine, 2-mercaptopyrimidine, 4-mercaptopyrimidine, uracil, C5-alkylpyrimidines, C5-benzylpyrimidines, C5-halopyrimidines, C5-vinylpyrimidine, pyrimidine C5-acetylenic, C5-acylpyrimidine, C5-amidopyrimidine, C5 -cyanopyrimidine, C5-nitropyrimidine, C5-aminopyrimidine, 5-azacytidinyl, 5-azauration, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, or a pharmaceutically acceptable derivative thereof. 17. A process according to claim 3, further characterized in that R2 is: where W is halogen, alkyl of 1 to 16 carbon atoms, alkoxyalkyl of 2 to 16 carbon atoms, aryl of 6 to 10 carbon atoms, alkoxy of 1 to 16 carbon atoms or nitro; or where E is aryl of 6 to 10 carbon atoms, alkoxy of 1 to 16 carbon atoms, alkoxyalkyl of 2 to 16 carbon atoms or alkyl of 1 to 16 carbon atoms; or Si (Z1) (Z2) (Z3), where Z1, Z2 and Z3 are independently selected from the group consisting of hydrogen, alkyl of 1 to 20 carbon atoms, optionally substituted with fluorine, bromine, chlorine, iodine; aralalkyl of 7 to 10 carbon atoms, optionally substituted with fluorine, bromine, chlorine or iodine; and aryl of 6 to 10 carbon atoms, optionally substituted with fluorine, bromine, chlorine or iodine.